Science of Synthesis

Science of Synthesis is the authoritative and comprehensive reference work for the entire field of organic and organometallic synthesis.

Science of Synthesis presents the important synthetic methods for all classes of compounds and includes:

Methods critically evaluated by leading scientists

Background information and detailed experimental procedures

Schemes and tables which illustrate the reaction scope

Preface

As the pace and breadth of research intensifies, organic synthesis is playing an increasingly central role in the discovery process within all imaginable areas of science: from pharmaceuticals, agrochemicals, and materials science to areas of biology and physics, the most impactful investigations are becoming more and more molecular. As an enabling science, synthetic organic chemistry is uniquely poised to provide access to compounds with exciting and valuable new properties. Organic molecules of extreme complexity can, given expert knowledge, be prepared with exquisite efficiency and selectivity, allowing virtually any phenomenon to be probed at levels never before imagined. With ready access to materials of remarkable structural diversity, critical studies can be conducted that reveal the intimate workings of chemical, biological, or physical processes with stunning detail.

The sheer variety of chemical structural space required for these investigations and the design elements necessary to assemble molecular targets of increasing intricacy place extraordinary demands on the individual synthetic methods used. They must be robust and provide reliably high yields on both small and large scales, have broad applicability, and exhibit high selectivity. Increasingly, synthetic approaches to organic molecules must take into account environmental sustainability. Thus, atom economy and the overall environmental impact of the transformations are taking on increased importance.

The need to provide a dependable source of information on evaluated synthetic methods in organic chemistry embracing these characteristics was first acknowledged over 100 years ago, when the highly regarded reference source Houben–Weyl Methoden der Organischen Chemie was first introduced. Recognizing the necessity to provide a modernized, comprehensive, and critical assessment of synthetic organic chemistry, in 2000 Thieme launched Science of Synthesis, Houben–Weyl Methods of Molecular Transformations. This effort, assembled by almost 1000 leading experts from both industry and academia, provides a balanced and critical analysis of the entire literature from the early 1800s until the year of publication. The accompanying online version of Science of Synthesis provides text, structure, substructure, and reaction searching capabilities by a powerful, yet easy-to-use, intuitive interface.

From 2010 onward, Science of Synthesis is being updated quarterly with high-quality content via Science of Synthesis Knowledge Updates. The goal of the Science of Synthesis Knowledge Updates is to provide a continuous review of the field of synthetic organic chemistry, with an eye toward evaluating and analyzing significant new developments in synthetic methods. A list of stringent criteria for inclusion of each synthetic transformation ensures that only the best and most reliable synthetic methods are incorporated. These efforts guarantee that Science of Synthesis will continue to be the most up-to-date electronic database available for the documentation of validated synthetic methods.

Also from 2010, Science of Synthesis includes the Science of Synthesis Reference Library, comprising volumes covering special topics of organic chemistry in a modular fashion, with six main classifications: (1) Classical, (2) Advances, (3) Transformations, (4) Applications, (5) Structures, and (6) Techniques. Titles will include Stereoselective Synthesis, Water in Organic Synthesis, and Asymmetric Organocatalysis, among others. With expert-evaluated content focusing on subjects of particular current interest, the Science of Synthesis Reference Library complements the Science of Synthesis Knowledge Updates, to make Science of Synthesis the complete information source for the modern synthetic chemist.

The overarching goal of the Science of Synthesis Editorial Board is to make the suite of Science of Synthesis resources the first and foremost focal point for critically evaluated information on chemical transformations for those individuals involved in the design and construction of organic molecules.

Throughout the years, the chemical community has benefited tremendously from the outstanding contribution of hundreds of highly dedicated expert authors who have devoted their energies and intellectual capital to these projects. We thank all of these individuals for the heroic efforts they have made throughout the entire publication process to make Science of Synthesis a reference work of the highest integrity and quality.

July 2010

The Editorial Board

E. M. Carreira (Zurich, Switzerland)

C. P. Decicco (Princeton, USA)

A. Fuerstner (Muelheim, Germany)

G. A. Molander (Philadelphia, USA)

P. J. Reider (Princeton, USA)

E. Schaumann (Clausthal-Zellerfeld, Germany)

M. Shibasaki (Tokyo, Japan)

E. J. Thomas (Manchester, UK)

B. M. Trost (Stanford, USA)

Abstracts

7.6.5.6 Aryl Grignard Reagents

H. Yorimitsu

Halogen–magnesium exchange between aryl iodides or bromides and an isopropylmagnesium chloride–lithium chloride complex or lithium trialkylmagnesates is now recognized as a useful method for the preparation of aryl Grignard reagents in addition to the conventional Grignard method. The exchange reactions lead to a wide variety of functionalized aryl Grignard reagents containing, for example, a carbonyl or a cyano group. Directed ortho-magnesiation reactions of arenes with bulky magnesium amide complexes, such as (2,2,6,6-tetramethylpiperidin-1-yl)magnesium chloride–lithium chloride complex and bis(2,2,6,6-tetramethylpiperidin-1-yl)magnesium–bis(lithium chloride) complex, are also useful.

Keywords: amination · “ate” complexes · carbomagnesiation · carbometalation · Grignard reagents · homocoupling · magnesates · magnesium compounds · metalation

7.6.10.9 Alkyl Grignard Reagents

H. Yorimitsu

While the conventional preparation of Grignard reagents from alkyl halides and metallic magnesium remains reliable, halogen–magnesium and sulfoxide–magnesium exchange have emerged as useful methods for the preparation of functionalized alkyl Grignard reagents that are otherwise difficult to synthesize. Carbomagnesiation reactions of alkenes are also useful for preparing alkyl Grignard reagents of some complexity. The formation of “ate” complexes gives a significant improvement in the utility of alkyl Grignard reagents and can lead to higher efficiency in nucleophilic addition to carbonyl compounds.

Keywords: “ate” complexes · carbomagnesiation · carbometalation · cyclization · magnesium compounds · magnesates · metalation · Grignard reagents · nucleophilic addition · sulfoxides

7.6.12.13 Magnesium Halides

M. Shimizu

This manuscript is an update to the earlier Science of Synthesis contribution describing reactions involving magnesium halides. It focuses on the literature published in the period 2001–2009. In particular, magnesium bromide and magnesium iodide are used frequently as promoters for specific transformations of important molecules.

Keywords: Friedel–Crafts reaction · Knoevenagel reaction · magnesium bromide · magnesium chloride · magnesium enolates · magnesium fluoride · magnesium iodide · Morita–Baylis–Hillman reaction

7.6.13.17 Magnesium Oxide, Alkoxides, and Carboxylates

M. Shimizu

This manuscript is an update to the earlier Science of Synthesis contribution describing reactions involving magnesium oxide, alkoxides, and carboxylates. It focuses on the literature published in the period 2001–2009. In particular, magnesium oxide and magnesium alkoxides are used for useful chemoselective transformations.

Keywords: Baeyer–Villiger oxidation · Diels–Alder reaction · ethyl magnesium malonate · magnesium alkoxides · magnesium bis[2-(alkoxycarbonyl)acetate] · magnesium carboxylates · magnesium monoperoxyphthalate · magnesium oxide · Mannich-type reaction · Michael addition · Oppenauer oxidation

7.6.14 Product Subclass 14: Magnesium Amides

M. Shimizu

This manuscript is a revision of the earlier Science of Synthesis contribution describing reactions involving magnesium amides. Synthesis of a series of magnesium amides, bis(amides), and their lithium chloride complexes is described. The use of magnesium amides as bases enables the regioselective deprotonation of a variety of molecules. Chiral magnesium amides are also discussed.

Keywords: amidomagnesium halide–lithium chloride complexes · amidomagnesium halides · magnesium bis(amide)–lithium chloride complexes · magnesium bis(amides) · magnesium dialkylamides · deprotonation

11.12.5 Oxazoles

A. Khartulyari and M. E. Maier

This manuscript is an update to the earlier Science of Synthesis contribution describing methods for the synthesis of oxazoles. This heterocyclic system is of particular interest, since many oxazole-containing natural products and their synthetic analogues possess interesting biological activities. In addition, oxazoles and related compounds serve as building blocks and reagents for organic synthesis.

Keywords: oxazoles · cyclization · multicomponent reaction · gold catalysis · heterocycles · N-propargylamides · cycloisomerization · coupling reactions

29.6.2 Acyclic and Semicyclic O/O Acetals

L. S. Fowler and A. Sutherland

This manuscript is an update to the previous Science of Synthesis contribution describing methods for the synthesis of acyclic and semicyclic acetals. It focuses on the literature published in the period 2007 to mid-2010.

Keywords: acyclic acetals · semicyclic acetals · aldehydes · ketones · trialkyl orthoformates · enol ethers · cycloaddition · dehydration · acetalization

29.7.3 1,3-Dioxetanes and 1,3-Dioxolanes

D. Carbery

This manuscript is an update to the earlier Science of Synthesis contribution describing methods for the synthesis of 1,3-dioxetanes and 1,3-dioxolanes. It focuses on the synthesis and synthetic applications of 1,3-dioxolanes covered in the literature over the period 2008–2010.

Keywords: dioxolane · carbonyls · diols · protecting groups · deprotection

29.9.2 Spiroketals

E. A. Anderson and B. Gockel

This manuscript is an update to the earlier Science of Synthesis contribution describing methods for the synthesis of spiroketals. It focuses on the literature published in the period 2005–2010.

Keywords: spiroketal · acetalization · benzannulation · carbon–-oxygen bonds · cyclic compounds · diastereoselectivity · intramolecular reactions · oxiranes · oxygen heterocycles · synthesis design · spiro compounds

29.16 Product Class 16: Glycosyl Oxygen Compounds (Di- and Oligosaccharides)

A. V. Demchenko and C. De Meo

This manuscript is a revision of the earlier Science of Synthesis contribution describing methods for the synthesis of di- and oligosaccharides. Recent new developments and important improvements of fundamental concepts are the particular focus of this update.

Keywords: carbohydrates · enzyme catalysis · glycosidases · glycosidation · glycosides · glycosylation · halides · imidates · neighboring-group participation · neuraminic acids · nucleophilic substitution · oligosaccharides · protecting groups · solid-phase synthesis · saccharides · stereoselective synthesis · sugars · thioglycosides · thioimidates

29.17 Product Class 17: Acyclic Hemiacetals, Lactols, and Carbonyl Hydrates

S. C. Coote, L. H. S. Smith, and D. J. Procter

Acyclic hemiacetals are in most cases unstable and exist only as transient intermediates, in contrast with cyclic hemiacetals (lactols), which are often stable, isolable compounds. Lactols may be prepared using various different methods, including the reduction of lactones, reduction of dicarbonyl compounds, or the selective oxidation of diols, as well as by addition of carbon nucleophiles to lactones or dicarbonyl compounds, deprotection of O-protected cyclic hemiacetals, or from enol ethers. Carbonyl hydrates are generally short-lived intermediates, although a limited number of stable carbonyl hydrates (generally derived from strained carbonyl compounds or carbonyl compounds bearing electron-withdrawing groups) have been documented.

Keywords: carbonyl additions · carbonyl compounds · dicarbonyl compounds · diols · hydroxycarbonyl compounds · lactols · lactonization · oxidation · reduction

29.18 Product Class 18: 1,1-Diacyloxy Compounds

L. H. S. Smith, S. C. Coote, and D. J. Procter

1,1-Diacyloxy compounds can be accessed from a variety of starting materials including aldehydes, ketones, and O/O, O/Hal, and Hal/Hal acetals under a variety of reaction conditions. This product class encompasses Meldrum's acid, several natural products, and acyloxy ester prodrugs; in addition, acyl acetals are useful protecting groups for aldehydes and can be cleaved orthogonally to alkyl acetals.

Keywords: acetals · acylation · alkylation · carbonyl compounds · carboxylic acids · esters · Lewis acid catalysts · oxidation

Table of Contents

Volume 7: Compounds of Groups 13 and 2 (Al, Ga, In, Tl, Be … Ba)

7.6 Product Class 6: Magnesium Compounds

7.6.5.6 Aryl Grignard Reagents

H. Yorimitsu

7.6.5.6 Aryl Grignard Reagents

7.6.5.6.1 Method 1: Synthesis by Reaction of Aryl Halides and Magnesium in the Presence of Lithium Chloride

7.6.5.6.2 Method 2: Synthesis by Halogen–Magnesium Exchange with Alkyl Grignard Reagents

7.6.5.6.2.1 Variation 1: Synthesis by Halogen–Magnesium Exchange with Lithium Triorganomagnesates

7.6.5.6.3 Method 3: Synthesis by Deprotonative ortho-Magnesiation

7.6.5.6.4 Method 4: Application to Synthesis of Biaryls by Dimerization

7.6.5.6.5 Method 5: Application to Synthesis of Amines

7.6.5.6.6 Method 6: Application to Addition to C—C Multiple Bonds Bearing a Directing Group

7.6.5.6.7 Method 7: Application to Transmetalations with Metal Halides

7.6.5.6.8 Method 8: Application to Addition to Carbonyl Compounds

7.6.5.6.8.1 Variation 1: Highly Efficient Addition of Lithium Triphenylmagnesate to Benzophenone

7.6.5.6.8.2 Variation 2: Zinc(II)-Catalyzed Addition of Aryl Grignard Reagents to Carbonyl Species

7.6.10.9 Alkyl Grignard Reagents

H. Yorimitsu

7.6.10.9 Alkyl Grignard Reagents

7.6.10.9.1 Method 1: Synthesis by Halogen–Magnesium Exchange

7.6.10.9.1.1 Variation 1: Synthesis by Sulfoxide–Magnesium Exchange

7.6.10.9.2 Method 2: Synthesis by Carbomagnesiation of C—C Multiple Bonds

7.6.10.9.3 Method 3: Application to Addition to Carbonyl Compounds

7.6.10.9.3.1 Variation 1: Highly Efficient Addition of Lithium Trialkylmagnesates to Acetophenone

7.6.10.9.3.2 Variation 2: Zinc(II)-Catalyzed Addition of Alkyl Grignard Reagents to Carbonyl Groups

7.6.12.13 Magnesium Halides

M. Shimizu

7.6.12.13 Magnesium Halides

7.6.12.13.1 Method 1: Applications of Magnesium Fluoride

7.6.12.13.1.1 Variation 1: Magnesium Fluoride Catalyzed Knoevenagel Reactions

7.6.12.13.1.2 Variation 2: Magnesium Fluoride/Chiral Phosphoric Acid Catalyzed Friedel–Crafts Reactions

7.6.12.13.2 Method 2: Applications of Magnesium Chloride as a Lewis Acid

7.6.12.13.2.1 Variation 1: Magnesium Chloride Promoted Claisen Reactions

7.6.12.13.2.2 Variation 2: Magnesium Chloride/Potassium Borohydride Promoted Reductions

7.6.12.13.3 Method 3: Applications of Other Magnesium Halides as Lewis Acids

7.6.12.13.3.1 Variation 1: Reaction of Organometallics in the Presence of Magnesium Bromide

7.6.12.13.3.2 Variation 2: Magnesium Halide Promoted Dipolar Cycloaddition Reactions

7.6.12.13.4 Method 4: Applications of Magnesium Halide/Base Systems to Enolate Formation and Subsequent Addition Reactions

7.6.12.13.5 Method 5: Applications of Magnesium Halides in Morita–Baylis–Hillman Reactions

7.6.12.13.6 Method 6: Applications of Magnesium Iodide in Ring-Expansion Reactions

7.6.13.17 Magnesium Oxide, Alkoxides, and Carboxylates

M. Shimizu

7.6.13.17 Magnesium Oxide, Alkoxides, and Carboxylates

7.6.13.17.1 Method 1: Applications of Magnesium Oxide

7.6.13.17.2 Method 2: Applications of Magnesium Methoxide as a Base

7.6.13.17.3 Method 3: Applications of Magnesium Alkoxides to the Oppenauer Oxidation

7.6.13.17.4 Method 4: Applications of Magnesium Alkoxides in Diastereo- and Enantioselective Reactions

7.6.13.17.5 Method 5: Applications of Magnesium Alkoxides in Elimination Reactions

7.6.13.17.6 Method 6: Applications of Magnesium Carboxylates

7.6.13.17.7 Method 7: Applications of Magnesium Monoperoxyphthalate

7.6.14 Product Subclass 14: Magnesium Amides

M. Shimizu

7.6.14 Product Subclass 14: Magnesium Amides

Synthesis of Product Subclass 14

7.6.14.1 Method 1: Synthesis of Methylmagnesium N-Cyclohexyl-N-isopropylamide

7.6.14.2 Method 2: Synthesis of (2,2,6,6-Tetramethylpiperidino)magnesium Chloride–Lithium Chloride Complex

7.6.14.3 Method 3: Synthesis of Magnesium Bis(diisopropylamide)

7.6.14.4 Method 4: Synthesis of Magnesium Bis(2,2,6,6-tetramethylpiperidide)

7.6.14.4.1 Variation 1: Synthesis of Magnesium Bis(2,2,6,6-tetramethylpiperidide)–Bis(lithium chloride) Complex

7.6.14.5 Method 5: Synthesis of Other Magnesium Bis(amide)s

7.6.14.6 Method 6: Synthesis of Chiral Magnesium Bis(dialkylamide)s

Applications of Product Subclass 14 in Organic Synthesis

7.6.14.7 Method 7: Reactions Involving Methylmagnesium N-Cyclohexyl-N-isopropylamide

7.6.14.8 Method 8: Reactions Involving (Diisopropylamino)magnesium Bromide

7.6.14.9 Method 9: Reactions Involving (2,2,6,6-Tetramethylpiperidino)magnesium Chloride–Lithium Chloride Complex

7.6.14.10 Method 10: Reactions Involving Magnesium Bis(diisopropylamide)

7.6.14.11 Method 11: Reactions Involving Magnesium Bis(2,2,6,6-tetramethylpiperidide)

7.6.14.12 Method 12: Reactions Involving Magnesium Bis(2,2,6,6-tetramethylpiperidide)–Bis(lithium chloride) Complex

7.6.14.13 Method 13: Reactions Involving Other Magnesium Bis(amide)s

7.6.14.14 Method 14: Reactions Involving Chiral Magnesium Bis(dialkylamide)s

Volume 11: Five-Membered Hetarenes with One Chalcogen and One Additional Heteroatom

11.12 Product Class 12: Oxazoles

11.12.5 Oxazoles

A. Khartulyari and M. E. Maier

11.12.5 Oxazoles

11.12.5.1 Synthesis by Ring-Closure Reactions

11.12.5.1.1 By Formation of One O—C and One N—C Bond

11.12.5.1.1.1 Fragments O—C—N and C—C

11.12.5.1.1.1.1 Method 1: From Vinyl Halides and Amides

11.12.5.1.1.2 Fragments O—C—C and C—N

11.12.5.1.1.2.1 Method 1: From Carbonyl Compounds and Nitriles

11.12.5.1.1.2.2 Method 2: From Acylcarbenes and Nitriles

11.12.5.1.1.2.3 Method 3: From Benzylamines and 1,3-Dicarbonyl Compounds

11.12.5.1.1.2.4 Method 4: From Amides and Propargylic Alcohols

11.12.5.1.1.3 Fragments N—C—C and C—O

11.12.5.1.1.3.1 Method 1: From 2-Amino-1-bromoethanesulfonamide and Acid Chlorides

11.12.5.1.1.4 Fragments O—C—C—N and C

11.12.5.1.1.4.1 Method 1: From Nitroethanones and Orthobenzoate

11.12.5.1.1.4.2 Method 2: From α-Cyano-β-hydroxy Enamines and Orthoformate

11.12.5.1.2 By Formation of One O—C and One C—C Bond

11.12.5.1.2.1 Fragments C—N—C and C—O

11.12.5.1.2.1.1 Method 1: From Isocyanides and Acyl Chlorides

11.12.5.1.3 By Formation of One O—C Bond

11.12.5.1.3.1 Fragment O—C—N—C—C

11.12.5.1.3.1.1 Method 1: Cyclodehydration of α-Acylamino Aldehydes or Ketones

11.12.5.1.3.1.2 Method 2: From (Acylamino)acetaldehyde Dimethyl Acetals

11.12.5.1.3.1.3 Method 3: From Oxazolones via Friedel–Crafts Acylation and Subsequent Cyclization

11.12.5.1.3.1.4 Method 4: Oxazoles from N-Propargylamides

11.12.5.1.3.1.5 Method 5: From Enamides

11.12.5.1.3.1.6 Method 6: From Amides and Diazocarbonyl Compounds

11.12.5.1.3.2 Fragment O—C—C—N—C

11.12.5.1.3.2.1 Method 1: Oxidative Cyclization of Schiff Bases Derived from Glycine Methyl Ester

11.12.5.1.3.2.2 Method 2: From Isocyanoacetamides and Imines

11.12.5.1.3.2.3 Method 3: Trifluoromethanesulfonic Anhydride Mediated Cyclocondensation of N-Acyl Amino Acid Esters

11.12.5.1.3.2.4 Method 4: From Aldehydes and Isocyanides

11.12.5.2 Aromatization

11.12.5.2.1 Method 1: By Dehydrogenation of Dihydrooxazoles

11.12.5.2.2 Method 2: Elimination of Hydrogen Chloride from Dihydrooxazoles

11.12.5.3 Synthesis by Substituent Modification

11.12.5.3.1 Substitution Reactions

11.12.5.3.1.1 Method 1: Reactions of Metalated Oxazoles with Electrophiles

11.12.5.3.1.2 Method 2: Oxazoles via Substitution of Leaving Groups through Transition-Metal-Catalyzed Reactions

11.12.5.3.1.3 Method 3: Coupling Reactions of Oxazolones

11.12.5.4 Applications of Oxazoles in Organic Synthesis

Volume 29: Acetals: Hal/X and O/O, S, Se, Te

29.6 Product Class 6: Acyclic and Semicyclic O/O Acetals

29.6.2 Acyclic and Semicyclic O/O Acetals

L. S. Fowler and A. Sutherland

29.6.2 Acyclic and Semicyclic O/O Acetals

29.6.2.1 Synthesis from Compounds of Higher Oxidation State

29.6.2.1.1 Method 1: Synthesis by Cycloaddition of Ketene Acetals

29.6.2.1.1.1 Variation 1: From Ketene Acetals and Alkenes via Cycloaddition

29.6.2.1.1.2 Variation 2: From Ketene Acetals and Alkynes via Cycloaddition

29.6.2.2 Synthesis from Compounds of the Same Oxidation State

29.6.2.2.1 Method 1: Synthesis from Hal/OR Acetals

29.6.2.2.2 Method 2: Synthesis from Aldehydes or Ketones and Alcohols

29.6.2.2.2.1 Variation 1: From Alcohols without Removal of Water

29.6.2.2.2.2 Variation 2: From Alcohols with Removal of Water by Physical Methods

29.6.2.2.2.3 Variation 3: From Alcohols with Removal of Water by Chemical Means

29.6.2.2.2.4 Variation 4: From Hemiacetals and Alkylating Agents

29.6.2.2.2.5 Variation 5: From Alcohols and Alkenyl Ketones

29.6.2.2.3 Method 3: Synthesis from Aldehydes or Ketones and Alcohol Derivatives

29.6.2.2.3.1 Variation 1: From Trialkyl Orthoformates

29.6.2.2.3.2 Variation 2: From Other Acetals

29.6.2.2.4 Method 4: Synthesis from Other O/O Acetals

29.6.2.2.4.1 Variation 1: By Exchange of Both Alkoxy Groups

29.6.2.2.4.2 Variation 2: By Exchange of One Alkoxy Group

29.6.2.2.5 Method 5: Synthesis from Acetals with Other Heteroatoms

29.6.2.2.5.1 Variation 1: From O/Se Acetals

29.6.2.2.5.2 Variation 2: From S/S Acetals

29.6.2.2.6 Method 6: Synthesis from Oximes

29.6.2.2.7 Method 7: Synthesis from Heterosubstituted Alkenes

29.6.2.2.7.1 Variation 1: From Acyclic Enol Ethers and Alcohols

29.6.2.2.7.2 Variation 2: From Cyclic Enol Ethers and Alcohols

29.6.2.2.7.3 Variation 3: From Allenyl Ethers and Alcohols

29.6.2.2.7.4 Variation 4: Dimerization of Enol Ethers

29.6.2.2.7.5 Variation 5: From Enol Ethers and Cyclic Carbonyl Ylides

29.6.2.3 Synthesis from Compounds of Lower Oxidation State

29.6.2.3.1 Method 1: Synthesis from Heterosubstituted Alkanes

29.6.2.3.1.1 Variation 1: From Alcohols

29.6.2.3.1.2 Variation 2: From Alcohols and Ethers

29.6.2.3.1.3 Variation 3: From Alcohols and Alkyl Halides

29.6.2.3.2 Method 2: Synthesis from Alkynes with Electron-Withdrawing Substituents

29.6.2.3.3 Method 3: Synthesis from Alkenes

29.6.2.3.4 Method 4: Synthesis from Peroxy Esters

29.7 Product Class 7: 1,3-Dioxetanes and 1,3-Dioxolanes

29.7.3 1,3-Dioxetanes and 1,3-Dioxolanes

D. Carbery

29.7.3 1,3-Dioxetanes and 1,3-Dioxolanes

29.7.3.1 1,3-Dioxetanes

29.7.3.2 1,3-Dioxolanes

29.7.3.2.1 Method 1: Synthesis by Formation of Two C—O Bonds

29.7.3.2.1.1 Variation 1: Reactions of Carbonyl Compounds with 1,2-Diols

29.7.3.2.1.2 Variation 2: Reactions of Acetals and Ketals with 1,2-Diols

29.7.3.2.1.3 Variation 3: Reactions of Enol Ethers with 1,2-Diols

29.7.3.2.1.4 Variation 4: Reactions of Carbonyl Compounds with 1,2-Bis(trimethylsilyl) Ethers

29.7.3.2.1.5 Variation 5: Reactions of Epoxides with Ketones

29.7.3.2.1.6 Variation 6: By Double Michael Addition of 1,2-Diols to Electron-Deficient Alkynes

29.7.3.2.1.7 Variation 7: Reaction of 1,1-Dihalo Compounds with 1,2-Diols

29.7.3.2.1.8 Variation 8: Reactions of Ketones and 2-Halo Alcohols

29.7.3.2.2 Method 2: Synthesis by Formation of One C—O Bond

29.7.3.2.2.1 Variation 1: From Monoprotected 1,2-Diols

29.7.3.2.2.2 Variation 2: By Oxidation of Electron-Rich Arenes and Hetarenes and Cyclization

29.7.3.2.2.3 Variation 3: By Cyclization of Hydroxy-Substituted Enol Ethers

29.7.3.2.2.4 Variation 4: By Intramolecular Transacetalization

29.7.3.2.2.5 Variation 5: Additions to Activated Alkenes

29.7.3.2.3 Method 3: Exchange of Ligands on Existing Acetals

29.7.3.2.3.1 Variation 1: Radical Reactions

29.7.3.2.3.2 Variation 2: From Metalated Dioxolanes

29.7.3.2.3.3 Variation 3: From Ortho Esters

29.7.3.2.4 Method 4: Deprotection Reactions of 1,3-Dioxolanes

29.7.3.2.5 Method 5: Applications of Chiral 1,3-Dioxolanes in Asymmetric Synthesis

29.9 Product Class 9: Spiroketals

29.9.2 Spiroketals

E. A. Anderson and B. Gockel

29.9.2 Spiroketals

29.9.2.1 Synthesis by Formation of Two C—O Bonds: Cyclization of Dihydroxy Ketones

29.9.2.1.1 Method 1: Nucleophilic Addition to Aldehydes

29.9.2.1.1.1 Variation 1: Using Dithiane-Stabilized Carbanions

29.9.2.1.1.2 Variation 2: Using Lithiated Methoxyallene Followed by Heck Reaction

29.9.2.1.2 Method 2: [3 + 2] Cycloaddition of Nitrile Oxides Followed by Dihydroisoxazole Hydrogenolysis

29.9.2.1.3 Method 3: Reductive Cross Coupling Followed by Oxidative Cleavage

29.9.2.1.4 Method 4: Radical Addition of Xanthates to Alkenes

29.9.2.1.5 Method 5: Kulinkovich Cyclopropanation of Esters Followed by Cyclopropanol Ring Opening

29.9.2.1.6 Method 6: Synthesis from Formyl Dianion Equivalents

29.9.2.1.6.1 Variation 1: Using Tosylmethyl Isocyanide Followed by Hydrolysis

29.9.2.1.6.2 Variation 2: Using Nitroalkanes Followed by Nef Reaction

29.9.2.2 Synthesis by Formation of Two C—O Bonds: Synthesis from Other Precursors

29.9.2.2.1 Method 1: Transition-Metal-Catalyzed Cyclizations

29.9.2.2.1.1 Variation 1: Palladium-Catalyzed Alkyne Cycloisomerization

29.9.2.2.1.2 Variation 2: Gold-Catalyzed Alkyne Cycloisomerization

29.9.2.2.1.3 Variation 3: Alkyne Cycloisomerization Catalyzed by Other Metals

29.9.2.2.1.4 Variation 4: Iron-Catalyzed Cyclization of Hydroxy Oxo Allylic Acetates

29.9.2.2.2 Method 2: Oxidative Cyclization of Phenols

29.9.2.2.3 Method 3: Oxidative Rearrangement of Alkyl Enol Ethers

29.9.2.2.4 Method 4: Iodoetherification of Dihydroxyalkenes Followed by Dehydroiodination

29.9.2.3 Synthesis by Formation of One C—O Bond and One C—C Bond

29.9.2.3.1 Method 1: Cycloaddition Reactions

29.9.2.3.1.1 Variation 1: Hetero-Diels–Alder Reactions of o-Quinomethanes

29.9.2.3.1.2 Variation 2: [3 + 2] Cycloadditions

29.9.2.3.2 Method 2: Metal-Catalyzed Cross Coupling

29.9.2.3.3 Method 3: Propargyl Claisen Rearrangement

29.9.2.4 Synthesis by Formation of One C—O Bond

29.9.2.4.1 Method 1: Oxidative Insertion

29.9.2.4.2 Method 2: Synthesis from Exocyclic Vinyl Ethers

29.9.2.4.2.1 Variation 1: Using Metal Carbenoids

29.9.2.4.2.2 Variation 2: Ring Expansion of Donor–Acceptor-Substituted Cyclopropanes

29.9.2.4.3 Method 3: Oxidation of Furans

29.9.2.4.3.1 Variation 1: Photooxygenation of Furans

29.9.2.4.3.2 Variation 2: Other Oxidation Reagents

29.9.2.4.4 Method 4: Lewis Acid Catalyzed 1,5-Hydride Transfer

29.9.2.5 Synthesis by Formation of One C—C Bond

29.9.2.5.1 Method 1: Reductive Cyclization of Cyano Acetals

29.9.2.5.2 Method 2: [2 +2+2] Cyclotrimerization

29.9.2.6 Synthesis by Formation of Two C—O Bonds and One C—C Bond

29.9.2.6.1 Method 1: Palladium-Catalyzed Three-Component Coupling

29.9.2.7 Synthesis of Spiroepoxides and Related Small-Ring Spiroketals

29.9.2.7.1 Method 1: Synthesis by Formation of Two C—O Bonds

29.9.2.7.2 Method 2: Synthesis by Formation of Four C—O Bonds

29.9.2.7.3 Method 3: Synthesis by Formation of One C—O Bond and One C—C Bond

29.9.2.8 Synthesis of Trioxadispiroketals

29.16 Product Class 16: Glycosyl Oxygen Compounds (Di- and Oligosaccharides)

A. V. Demchenko and C. De Meo

29.16 Product Class 16: Glycosyl Oxygen Compounds (Di- and Oligosaccharides)

29.16.1 Product Subclass 1: Disaccharides

29.16.1.1 Synthesis of Product Subclass 1

29.16.1.1.1 Method 1: Synthesis from Anomeric Halides

29.16.1.1.1.1 Variation 1: From Fluorides

29.16.1.1.1.2 Variation 2: From Chlorides and Bromides

29.16.1.1.1.3 Variation 3: From Iodides

29.16.1.1.2 Method 2: Synthesis from 1-Oxygen-Substituted Derivatives

29.16.1.1.2.1 Variation 1: From Hemiacetals

29.16.1.1.2.2 Variation 2: From O-Acyl, O-Carbonyl, and Related Compounds

29.16.1.1.2.3 Variation 3: From O-Imidates

29.16.1.1.2.4 Variation 4: From Phosphites, Phosphates, and Other O—P Derivatives

29.16.1.1.2.5 Variation 5: From O-Sulfonyl Derivatives

29.16.1.1.2.6 Variation 6: By O-Transglycosidation

29.16.1.1.3 Method 3: Synthesis from 1-Sulfur-Substituted Derivatives

29.16.1.1.3.1 Variation 1: From Alkylsulfanyl and Arylsulfanyl Glycosides (Thioglycosides)

29.16.1.1.3.2 Variation 2: From Thioimidates

29.16.1.1.3.3 Variation 3: From Sulfoxides, Sulfimides, and Sulfones

29.16.1.1.3.4 Variation 4: From Xanthates and Related Derivatives

29.16.1.1.3.5 Variation 5: From Thiocyanates and Other Thio Derivatives

29.16.1.1.4 Method 4: Synthesis from Miscellaneous Glycosyl Donors

29.16.1.1.4.1 Variation 1: From Ortho Esters and Dihydrooxazoles

29.16.1.1.4.2 Variation 2: From 1,2-Dehydro and 1,2-Anhydro Derivatives

29.16.1.1.4.3 Variation 3: From Seleno- and Telluroglycosides

29.16.1.1.4.4 Variation 4: From 1-Diazirine Derivatives

29.16.1.1.5 Method 5: Synthesis by Intramolecular and Indirect Methods

29.16.2 Product Subclass 2: Oligosaccharides

29.16.2.1 Synthesis of Product Subclass 2

29.16.2.1.1 Method 1: Linear Synthesis

29.16.2.1.2 Method 2: Block Synthesis

29.16.2.1.3 Method 3: Synthesis by Selective Activation

29.16.2.1.4 Method 4: Synthesis by Two-Step Activation and In Situ Preactivation

29.16.2.1.5 Method 5: Armed–Disarmed and Related Chemoselective Approaches

29.16.2.1.5.1 Variation 1: Arming and Disarming with Neighboring Substituents

29.16.2.1.5.2 Variation 2: Disarming with Remote Substituents

29.16.2.1.5.3 Variation 3: Disarming by Torsional Effects

29.16.2.1.5.4 Variation 4: Reactivity-Based Programmable Strategy

29.16.2.1.5.5 Variation 5: Superdisarmed Building Blocks

29.16.2.1.5.6 Variation 6: Superarmed Glycosyl Donors

29.16.2.1.6 Method 6: The Active–Latent Approach

29.16.2.1.7 Method 7: Steric Hindrance and Temporary Deactivation

29.16.2.1.8 Method 8: Orthogonal and Semi-Orthogonal Strategies

29.16.2.1.9 Method 9: One-Pot Strategies

29.16.2.1.10 Method 10: Regioselective and Other Acceptor-Reactivity-Based Concepts

29.16.2.1.11 Method 11: Polymer-Supported Synthesis

29.16.2.1.11.1 Variation 1: Automated Synthesis

29.16.2.1.12 Method 12: Fluorous Tag Supported, Ionic Liquid Supported, and Microreactor Synthesis

29.16.2.1.13 Method 13: Surface-Tethered Synthesis

29.16.2.1.14 Method 14: Enzymatic Synthesis

29.16.2.1.14.1 Variation 1: Using Glycosyltransferases

29.16.2.1.14.2 Variation 2: Using Glycosidases (Hydrolases)

29.17 Product Class 17: Acyclic Hemiacetals, Lactols, and Carbonyl Hydrates

S. C. Coote, L. H. S. Smith, and D. J. Procter

29.17 Product Class 17: Acyclic Hemiacetals, Lactols, and Carbonyl Hydrates

29.17.1 Product Subclass 1: Acyclic Hemiacetals

29.17.1.1 Synthesis of Product Subclass 1

29.17.1.1.1 Method 1: Synthesis from Aldehydes or Ketones by Addition of Alcohols

29.17.1.1.2 Method 2: Reduction of Esters

29.17.1.1.3 Method 3: Addition of Carbon Nucleophiles to Esters

29.17.1.1.3.1 Variation 1: Addition of Nucleophiles Bearing Stabilizing Groups

29.17.1.1.3.2 Variation 2: Addition of Nucleophiles Bearing Stabilizing Groups to Esters Bearing Stabilizing Groups

29.17.2 Product Subclass 2: Lactols

29.17.2.1 Synthesis of Product Subclass 2

29.17.2.1.1 Method 1: Reduction of Lactones

29.17.2.1.1.1 Variation 1: Using Diisobutylaluminum Hydride

29.17.2.1.1.2 Variation 2: Using Other Aluminum Hydride Reagents

29.17.2.1.1.3 Variation 3: Metal Hydride Catalyzed Hydrosilylation

29.17.2.1.1.4 Variation 4: Using Borohydride Reagents

29.17.2.1.2 Method 2: Addition of Carbon Nucleophiles to Lactones

29.17.2.1.2.1 Variation 1: Addition of Preformed Alkylmetal Reagents to Lactones

29.17.2.1.2.2 Variation 2: Barbier Additions to Lactones

29.17.2.1.3 Method 3: Oxidation of Diols

29.17.2.1.3.1 Variation 1: By Selective Oxidation of a Primary Hydroxy Group

29.17.2.1.3.2 Variation 2: By Selective Oxidation of a Secondary Hydroxy Group

29.17.2.1.3.3 Variation 3: By Selective Oxidation of Allylic and Benzylic Hydroxy Groups

29.17.2.1.4 Method 4: Reduction of Dicarbonyl Compounds

29.17.2.1.5 Method 5: Addition of Carbon Nucleophiles to Dicarbonyl Compounds

29.17.2.1.6 Method 6: Deprotection of Protected Cyclic Hemiacetals

29.17.2.1.6.1 Variation 1: Deprotection of O-Alkyl Lactols

29.17.2.1.6.2 Variation 2: Deprotection of O-Acyl Lactols

29.17.2.1.6.3 Variation 3: Deprotection of O-Silyl Lactols

29.17.2.1.7 Method 7: Synthesis From Enol Ethers

29.17.2.1.7.1 Variation 1: Acid-Catalyzed Hydration of Enol Ethers

29.17.2.1.7.2 Variation 2: Oxidation of Enol Ethers

29.17.2.1.8 Method 8: Oxidation of Cyclic Ethers

29.17.3 Product Subclass 3: Carbonyl Hydrates

29.17.3.1 Synthesis of Product Subclass 3

29.17.3.1.1 Method 1: Hydration of Carbonyl Compounds

29.17.3.1.1.1 Variation 1: Synthesis from Carbonyl Compounds Bearing Electron-Withdrawing Groups

29.17.3.1.1.2 Variation 2: Synthesis of Carbonyl Hydrates Stabilized by Hydrogen Bonding

29.17.3.1.1.3 Variation 3: Synthesis from Strained Ketones

29.17.3.1.2 Method 2: Oxidation of Activated Methyl or Methylene Groups

29.17.3.1.2.1 Variation 1: Oxidation Using Dimethyldioxirane

29.17.3.1.2.2 Variation 2: Oxidation Using Selenium Dioxide

29.17.3.1.2.3 Variation 3: Other Oxidations

29.18 Product Class 18: 1,1-Diacyloxy Compounds

L. H. S. Smith, S. C. Coote, and D. J. Procter

29.18 Product Class 18: 1,1-Diacyloxy Compounds

29.18.1 Synthesis of Product Class 18

29.18.1.1 Acylation of Carbonyl Compounds

29.18.1.1.1 Method 1: Acylation of Aldehydes

29.18.1.1.1.1 Variation 1: Using a Lewis Acid Catalyst

29.18.1.1.1.2 Variation 2: In the Absence of a Catalyst

29.18.1.1.2 Method 2: Acylation of Ketones

29.18.1.1.2.1 Variation 1: Synthesis of Meldrum's Acid Using a Diacid and a Ketone

29.18.1.1.2.2 Variation 2: Using an Oxo Acid

29.18.1.1.3 Method 3: Synthesis from 1-Acyloxy-1-hydroxy Compounds, Carbonyl Hydrates, or Vinyl Esters

29.18.1.2 Alkylation of Carboxy Groups

29.18.1.2.1 Method 1: Synthesis Using Hal/Hal Acetal Electrophiles

29.18.1.2.2 Method 2: Synthesis Using O/Hal Acetal Electrophiles

29.18.1.3 Oxidative Methods

29.18.1.3.1 Method 1: Synthesis Using Single-Electron-Transfer Reagents

29.18.1.3.1.1 Variation 1: Oxidation of Benzylic Methyl and Methylene Groups

29.18.1.3.2 Method 2: Other Oxidations

29.18.1.3.2.1 Variation 1: Baeyer–Villiger Oxidation of α-Acyloxy Ketones

29.18.1.3.2.2 Variation 2: Oxidation of Furan Derivatives

29.18.1.4 Synthesis from Propargyl Esters

Author Index

Abbreviations

7.6.5.6 Aryl Grignard Reagents (Update 2010)

H. Yorimitsu

General Introduction

The conventional preparation of aryl Grignard reagents from aryl halides and magnesium metal still remains the most important and convenient available method. However, an improved Grignard method was reported in 2008 utilizing lithium chloride as an additive (see ▶ Section 7.6.5.6.1). Recently, halogen–magnesium exchange between aryl halides and alkyl Grignard reagents has been attracting increasing attention as the exchange allows for preparation of functionalized aryl Grignard reagents such as cyano- and carbonyl-substituted species (see  ). Furthermore, deprotonation assisted by a directing group is also emerging as a useful method for the preparation of functionalized aryl Grignard reagents (see  ).

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